GABAergic System Impairment Worsens Seizures in Dravet Patients, Study Reveals

GABAergic System Impairment Worsens Seizures in Dravet Patients, Study Reveals

For the first time, researchers have described a dysfunction in the brain’s GABAergic system that could increase the frequency and severity of epileptic seizures in patients with Dravet syndrome.

The findings also highlight the therapeutic potential of cannabis derivatives, including cannabidiol, that are able to target GABAA receptors and restore the brain’s GABAergic function, alleviating epileptic seizures in heavily treated patients.

The study, “A novel GABAergic dysfunction in human Dravet syndrome,” was published in Epilepsia.

Dravet syndrome is a severe type of drug-resistance epilepsy that usually emerges during the first year of life and is characterized by seizures, cognitive deficits, and increased mortality.

Most patients (70-80%) carry genetic mutations in the SCN1A gene, which encodes for a subunit of a sodium channel essential for the generation and transmission of electrical signals in the brain.

Although defects in sodium channels are considered the primary cause for brain hyper-excitability leading to epileptic seizures in patients with Dravet syndrome, more recently it has been proposed that dysfunctions in the brain’s GABAergic system also may contribute to disease aggravation.
GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter, or neural signal, in the brain. It works by preventing excessive neuronal activity, after passing through specific channels located on the surface of neurons, called GABAA receptors.
These receptors consist of a central pore (the region through which ions flow) surrounded by five subunits (most often two alpha, two beta, and one gamma subunit).
GABAergic dysfunctions have been described in some patients with Dravet syndrome and in other neurological disorders, including Down syndrome, Rett syndrome and tuberous sclerosis complex (TSC), but so far the mechanisms underlying these GABAergic impairments in Dravet syndrome are not yet fully understood, partly due to the lack of patient brain tissue samples.
“To overcome the limited availability of DS [Dravet syndrome] tissues, one approach to study GABAergic transmission in rare human epileptic diseases is the microtransplantation of GABAARs [GABAA receptors] from human brain into Xenopus oocytes [frog eggs],” researchers wrote.
“The advantage of this technique is the possibility of investigating human GABAARs using a minimal amount of brain tissue of DS patients … It is noteworthy that the “microtransplanted” GABAARs retain their native characteristics,” they added.
In this study, researchers from the University of Rome used a technique called voltage-clamp to record the activity of GABAA receptors from post-mortem brain tissue samples of three patients with Dravet syndrome that were transplanted into frog eggs. Controls for comparison included brain samples from two TSC patients and three age-matched healthy control subjects.
Researchers found a significant decrease in GABA sensitivity in samples from patients with Dravet syndrome compared to healthy controls, which seem to be correlated with an increase in the number of GABAA receptors containing the alpha-4 subunit relative to alpha-1.
Remarkably, low doses of cannabidiol (CBD) increased GABA currents in brain samples from Dravet syndrome and TSC patients, comparable to those elicited by conventional benzodiazepines that bind with high affinity to GABAA receptors, such as flunitrazepam.

“A take‐home message from our results for clinicians is that CBD may restore GABAergic function and that DS patients could be treated with low doses of CBD, which have been proven also to ameliorate social behaviour in DS models,” researchers wrote.

“[W]e describe for the first time a new additional GABAergic dysfunction in DS that could exacerbate the occurrence and progression of [epileptic seizures]. Furthermore, this GABAergic defect as a feature of “brain dysmaturity” could be targeted by new therapeutic approaches with few side effects in these patients, who are already burdened by high drug load,” they concluded.

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